This application outlines a 5-year academic research career development plan in laboratory based epilepsy research. The applicant is a physician who also holds a Ph.D in Neuroscience. He has completed a residency in neurology and is currently completing a fellowship in clinical and research epileptology, all at the University of Arizona. Having laid the foundations for an academic career, the applicant will focus on developing experimental models of epilepsy under the mentorship of Robert Sloviter, Ph.D. The mentor has developed animal models of temporal lobe epilepsy and has over twenty years of experience performing and supervising research in this area. He will continue to provide the applicant with supervision and unrestricted resources in his laboratory. Hippocampal sclerosis, a common lesion associated with temporal lobe epilepsy, is often unilateral or asymmetric, and often occurs after relatively innocuous insults to the brain that do not cause widespread brain injury, as seen in current animal models of temporal lobe epilepsy. Novel human data suggest that pre-existing focal defects in hippocampal structure and function might amplify the effects of seizures or other insults on temporal lobe structures. Using continuous electrophysiological and behavioral monitoring in awake, chronically implanted rats, experiments will first determine the threshold for injury and epileptogenesis in normal rats following perforant path stimulation-induced status epilepticus. Following determination of the threshold for injury, the applicant will utilize newly developed and highly specific methods to selectively and focally destroy hippocampal inhibitory interneurons. The threshold for injury and epileptogenesis following seizures will then be determined in animals with unilateral and bilateral defects. The predictions that focal disinhibition will lower the threshold for inducing injury and epileptogenesis, and will induce asymmetric hippocampal damage with relative preservation of other brain regions, will facilitate development of rational models for understanding and developing treatments for temporal lobe epilepsy.